Infected for Life:
How Herpes Simplex Virus Uses MicroRNA to Hide Out in Cells

(Philadelphia, PA) – Researchers at the University
of Pennsylvania School of Medicine have discovered part of the
reason why cold sores, caused by a herpes virus, come back again and again.
The new study, published online last month in Nature, points
to a small RNA molecule, called a microRNA (miRNA) as the culprit that
keeps the latent virus-infected cell alive. These findings could one day
lead to a new way to fight the virus and offers the first target for intervention
in the latent infection.

A research team led by Nigel W. Fraser, PhD, Professor
of Microbiology, has found that herpes simplex virus-1 (HSV-1), the virus
that causes cold sores and ocular keratitis, produces an miRNA molecule.
This miRNA is encoded by the Latency-Associated Transcript gene (LAT)
in the viral genome and works through a process called RNA interference
to prevent normal cell death or apoptosis. Thus, the latent viral infection
is maintained for the lifetime of the individual because the latently
infected cell does not die."

“Although miRNAs encoded by cellular genes are known to be an important
mechanism for controlling gene expression, this is one of the first miRNA
found to be encoded by a viral genome,” says Fraser. “Our
study helps show how HSV-1 can maintain a latent infection for the lifetime
of an infected individual.”

The LAT gene was discovered by Fraser and colleagues in 1984, but a protein
product from this gene has never been found. This caused Fraser and his
research team to hypothesize that LAT may work through an miRNA molecule,
which is a small piece of the LAT gene. It interferes with the translation
of two cell proteins that are required for cell death: TGF-b and SMAD-3.
The LAT miRNA binds to specific sequences of messenger RNA from these
two genes and causes them to be degraded. Thus, the amount of TGF-b and
SMAD-3 protein is reduced in the cell and apoptosis is prevented. Because
the latent virus is not producing any viral proteins the immune system
of the infected individual cannot detect the infected cell.

Latent HSV-1 infections form in neuronal cells of the peripheral nervous
system. When a latent infection is reactivated (by stress of many kinds),
HSV-1 proteins are synthesized and new infectious virus particles are
formed. These virus particles migrate along the neuronal axons to the
epithelial cells of the skin. Viral growth in the skin, or other mucous
membranes where nerves are found, causes cell damage and an immune reaction
that results in a painful sore. Although the latency-to-reactivation process
is not fully understood, it is known to involve stress, such as physical
damage, ultraviolet light, hormones, or even fever.
Fraser is currently testing whether HSV-2, a relative of HSV-1 that causes
genital herpes, also encodes an miRNA molecule in its LAT gene. “MiRNA
may be a more general mechanism that latent viruses use to remain alive
in the host cell,” suggests Fraser.

Present treatments of HSV-1 rely on acyclovir-based drugs that target
the viral polymerase and inhibit viral DNA replication during the acute
infection. However, they do not target the latent infection, and thus
cold sores return throughout the lifetime of the infected individual.
Finding an miRNA that interacts with the cellular TGF-b pathway during
latency offers the first target against the latent infection and offers
a profoundly different approach to treatment, concludes Fraser.

The study co-authors are Ananya Gupta, Jarred J. Garner, Praveen Sethupathy,
and Artemis G. Hatzigeorgiou, all from Penn. The study was funded in part
by grants from the National Institutes of Health.

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